1. Field of the Invention
The present invention relates to 2,4-disubstituted-5-aminocarbonyl-1,3-thiazole derivatives for treating inflammatory diseases, a preparation method thereof, and a therapeutic agent for treating inflammatory diseases induced by SPC activity, which contains the derivatives as an active ingredient, and more particularly to 2,4-disubstituted-5-aminocarbonyl-1,3-thiazole derivatives, which are novel compounds showing SPC inhibitory activity, a preparation method thereof, and a therapeutic agent for treating inflammatory diseases induced by SPC activity, which contains the derivatives as an active ingredient.
2. Description of the Prior Art
Sphingosylphosphorylcholine (hereinafter referred to as “SPC”), together with sphingosine-1-phosphate (S1P) and lysophosphatidic acid (LPA) structurally similar thereto, is a member of the lysophospholipid class of phospholipids. These substances act as important signaling mediators in immune functions, such as cellular proliferation and migration, and inflammatory reactions.
SPC is produced from sphingomyelin (a component of the cell membrane) by sphingomyelin deacylase [Higuchi K, Biochem J., 2000, 350, 747-56]. Also, SPC is known to be deeply involved in the growth and proliferation of various cells [Desai, Biochem. Biophys. Res. Commun., 1991, 181, 361-366], angiogenesis [Boguslawski, Biochem. Biophys. Res. Commun., 2000, 272, 603-609], and apoptosis [Jeon E S, Biochim Biophys Acta., 2005, 1734(1); 25-33].
A typical example of SPC-related disease is atopic dermatitis. In atopic dermatitis, due to a decrease in the lipid content of the horny layer, antimicrobial activity is reduced and the skin's horny layer is weakened, and thus a defense against external stimuli is reduced, whereby inflammatory reactions occur, leading to itching. Moreover, itching causes secondary infection, thus causing hyper-immune responses.
Particularly, it is known that, in normal persons, SPC is not substantially present or is detected at very low concentrations, but it is increased several thousand times in the dermatitis of atopic dermatitis patients [Higuchi K, Biochem. J., 2000, 350, 747-756; Reiko Okamoto, Journal of Lipid Research, 2003, 44, 93-102]. The chief cause is the deficiency of ceramide in the horny layer of atopic dermatitis patients [Junko Hara, J. invest. Dermatol., 2000, 115, 406-413]. Also, SPC plays an important role in the altered keratinization process of epidermis in atopic diseases [Higuchi, J. Lipid Res., 2001, 42, 1562-1570]. Such study results suggest that SPC is the direct cause of skin barrier disruption, a typical symptom of atopic disease, and can cause secondary inflammatory reactions. Accordingly, a substance of controlling the production of SPC can be used as a therapeutic agent for treating skin inflammatory diseases.
Meanwhile, with respect to itching which causes the patient's pain and decreases the patient's life quality, among symptoms of atopic dermatitis, it was reported that lysophosphatidic acid (LPA) structurally similar to SPC causes itching [Hashimoto, Pharmacology, 2004, 72, 51-56]. Thus, it can be inferred that SPC can also cause itching in the body. In addition, it was recently demonstrated that intradermal injection of SPC can directly cause itching [International patent Publication Ser. No. 06/049,451].
The present inventors previously developed novel thiazole derivatives for treating inflammatory diseases induced by SPC activity [Korean. Patent Application No. 2007-97553].
Accordingly, the present inventors have screened novel compounds, which can be used as therapeutic agents for treating inflammatory diseases having improved efficiency, from N-{5-benzoyl-2-[4-(2-methoxyphenyl)piperazin-1-yl]thiazol-4-yl}pivalamide compounds among the above-mentioned thiazole derivatives. As a result, the present inventors have prepared 2,4-disubstituted-5-aminocarbonyl-1,3-thiazole derivative compounds through an improved solid-phase synthetic process, have examined the anti-inflammatory effects of the 2,4-disubstituted-5-aminocarbonyl-1,3-thiazole derivative compounds through a test employing human dermal cells and an animal test employing mice and, as a result, have found that the derivative compounds have excellent inflammation inhibitory effects, thereby completing the present invention.